We will investigate the molecular mechanisms responsible for the tissue specific and developmentally regulated hypermutation of immunoglobulin variable region genes. This will be done by introducing manipulated transfected genes into: 1) B cell lines whose endogenous immunoglobulin genes are constitutively unstable or whose instability is triggered by T cells and 2) transgenic mice. We will also study the role and impact of V region mutations and isotype switching on the immune response to viruses and fungi in normal mice and on the production of autoantibodies in lupus prone autoimmune mice. We will study the role of affinity and avidity in targeting to a model tumor system. We will use the insight gained from these studies to generate antibodies that can be passively administered to protect against HIV and cryptococcus infections and to target to drug resistant tumors.